PROJECT SUMMARY Neuroadaptive changes in gene expression due to repeated ethanol consumption is a major mechanism that underlies the transition from moderate to excessive drinking. Gene expression profiling studies of human alcoholics and ethanol dependent rodents have identified a multitude of ethanol-responsive gene networks. Little is known about how these networks are recruited into a neuroadaptive response. One mechanism could involve ethanol regulation of transcriptional co-regulators that bind and modulate the activity of several transcription factors, thereby orchestrating a diverse neuroadaptive transcriptional network. However, very few studies have identified transcriptional co-regulators in the brain that respond to ethanol and in turn regulate ethanol consumption. In ongoing experiments we found evidence that the transcriptional co-regulator Lim-only 4 (LMO4) regulates ethanol consumption. LMO4 is expressed in brain regions important for addiction and recent work indicates that it plays an important role in cocaine sensitization and conditioned reward for sucrose. Our initial results show that LMO4 levels in the nucleus accumbens decrease during intermittent, binge-like ethanol consumption, and a gene trap mutation in the Lmo4 gene, which reduces LMO4 levels by 50%, increases the development of excessive ethanol consumption in male C57BL/6J mice. Given these findings we propose that LMO4 is an ethanol-responsive, neuroadaptive transcriptional co-regulator that regulates ethanol consumption. This hypothesis will be addressed in two Specific Aims: (1) to determine whether LMO4 regulates ethanol consumption in both sexes, and (2) to identify brain regions in which LMO4 acts to moderate ethanol consumption. Should the results show that LMO4 in specific regions of the adult brain regulates ethanol consumption in male and female mice, future studies aimed at determining how ethanol regulates LMO4 and how LMO4 regulates ethanol consumption could shed new light on a fundamental mechanism by which ethanol provokes a neuroadaptive response that leads to excessive drinking.